Our current and future studies are centered around the Armenian hamster and its peculiar susceptibility to hepatic cancer after estrogen administration. In this animal, estrogen by itself initiates carcinogenesis and few animal models are available to study this direct carcinogenic effect of sex hormone. Epidemiological studies have clearly shown that diet influences the incidence of human breast and prostate cancer, and pathogenesis of both of these tumors is dependent on sex hormones. The scarcity of these tumors in Asian population may be explained by the paucity of fat and/or the plethora of soy flour in the Asian diet. Soy is an abundant source for phytoestrogens, constituents with a configuration permitting an interaction with estrogen receptor that could result in blocking or partial activation of the estrogen receptor. Accordingly, we are feeding Armenian hamsters various synthetic diets containing soy protein (or various semipurified phytoestrogens from soy), or casein protein and also diets with high fat content. Corn oil or rape seed oil were used to make high fat diets, containing 20% fat versus 5% fat in normal diets. Rape seed oil contains a high content (~ 40%) of erucic acid, a long chain monounsaturated fatty acid. There is some epidemiological evidence linking the use of rape seed oil for cooking with the high incidence of intrahepatic cholestasis of pregnancy in women in Chile and Sweden. For the estrogen challenge, we have been using Zeranol, (a synthetic resorcylic acid lactone derivative), available as an injectable or in pellet form. It is a natural estrogen produced by Fusarium fungi and is commonly found in the human diet because it is produced by the fungi contaminating grains. Also, the growth promoting (anabolic) effects of Zeranol have led to its widespread use as a growth stimulant in meat production. Zeranol is known as a weak estrogen, although in Armenian hamster it is effective in inducing acute icterus and followed by tumor formation with only minimal morbidity. After administration of Zeranol, the amount of hepatobilary dysfunction is evaluated by measuring hyperbilirubinemia in serial plasma samples. At this time, we are only measuring acute estrogenic effects on the liver, as previous experience indicates a direct relationship between magnitude of acute bilirubinemia and subsequent incidence of hepatic tumors. These dietary studies are currently in progress, however, it is clear at this time that the hepatic response to estrogen is definitely influenced by the diet of the hamsters. The standard laboratory chow uses protein from a variety of sources including fish meal, alfalfa, and various grains. When casein is used exclusively for protein in the diet, the adverse effect of estrogen on the liver is diminished. That is, casein acts to protect the liver of the Armenian hamster from the estrogen induced hepatobiliary dysfunction. If the fat content is increased (rape seed oil or corn oil) the affect of estrogen is further diminished, and the majority of animals actually show no effects (that is, hyperbilirubinemia, increased transaminase levels, etc.) from the estrogen challenge. These studies are showing that diet does indeed play a role in the ability of estrogen to activate an estrogen receptor effect in the hamster liver. At this time it is not known if this effect is mediated through expression or modulation of estrogen receptor or some other mechanism before or after estrogen receptor activation. These initial studies have focused on evaluating the influence of diet on acute toxic effects from estrogen. It is likely that diet will also protect these hamsters from hepatic cancer after chronic estrogen treatment, because previous data indicates a direct quantitative relationship between the acute toxic and chronic neoplastic phases.